Dr. Elias Sayour, Chong Zhao and Arnav Barpujari discuss the mRNA cancer vaccine developed at the University of Florida
Contrary to the bizarre antivaxxer claims that the mRNA vaccines used against the SARS-CoV-2 virus that causes COVID-19 somehow causes cancer, based on nothing more substantial than the fact that some people who developed cancer had previously been vaccinated, there is now an mRNA vaccine that is proving spectacularly effective against a highly malignant form of brain cancer.
Curiously, the fact that some people who developed cancer will previously have sung Christmas carols or eaten potatoes, is never given as a probable cause, but then few people who believe antivaxxer disinformation will understand statistics or statistical correlations.
The mRNA vaccine against the brain cancer known as Glioblastoma has shown very promising results in a small-scale study of four adults by scientists at Florida University, repeating the results of a trial in 10 dogs and preclinical trials in mice.
The vaccine successfully, and very quickly, reprograms the immune system to produce highly specific antibodies against the tumour. Intelligent design proponents (or 'cdesign proponentcists' as they have been known since the Kitzmiller trial) might like to explain why the immune system, supposedly intelligently designed to protect us, needs to be artificially reprogrammed by human medical science.
The trick has been to create clusters of nanoparticles of lipid-enclosed mRNA wrapped around one another like a miniature onion. These means the mRNA will be released slowly and reprogram the immune system more effectively than a single burst would. The specific mRNA is tailor-made for the patient's tumour and creates antibodies against specific tumor proteins, in the same way the mRNA anti-COVID vaccines target the virus's spike proteins, so is specific to that particular cancer.
The results are reported in the journal Cell and are also explained in a University of Florida Health News release:
In a first-ever human clinical trial of four adult patients, an mRNA cancer vaccine developed at the University of Florida quickly reprogrammed the immune system to attack glioblastoma, the most aggressive and lethal brain tumor.
The results mirror those in 10 pet dog patients suffering from naturally occurring brain tumors whose owners approved of their participation, as they had no other treatment options, as well as results from preclinical mouse models. The breakthrough now will be tested in a Phase 1 pediatric clinical trial for brain cancer.
Reported May 1 in the journal Cell, the discovery represents a potential new way to recruit the immune system to fight notoriously treatment-resistant cancers using an iteration of mRNA technology and lipid nanoparticles, similar to COVID-19 vaccines, but with two key differences: use of a patient’s own tumor cells to create a personalized vaccine, and a newly engineered complex delivery mechanism within the vaccine.
“Instead of us injecting single particles, we’re injecting clusters of particles that are wrapping around each other like onions, like a bag full of onions,” said senior author Elias Sayour, M.D., Ph.D., a UF Health pediatric oncologist who pioneered the new vaccine, which like other immunotherapies attempts to “educate” the immune system that a tumor is foreign. “And the reason we’ve done that in the context of cancer is these clusters alert the immune system in a much more profound way than single particles would.”
Among the most impressive findings was how quickly the new method, delivered intravenously, spurred a vigorous immune-system response to reject the tumor, said Sayour, principal investigator of the RNA Engineering Laboratory within UF’s Preston A. Wells Jr. Center for Brain Tumor Therapy and a UF Health Cancer Center and McKnight Brain Institute investigator who led the multi-institution research team.
“In less than 48 hours, we could see these tumors shifting from what we refer to as ‘cold’ — immune cold, very few immune cells, very silenced immune response — to ‘hot,’ very active immune response,” he said. “That was very surprising given how quick this happened, and what that told us is we were able to activate the early part of the immune system very rapidly against these cancers, and that’s critical to unlock the later effects of the immune response.”
Glioblastoma is among the most devastating diagnoses, with median survival around 15 months. Current standard of care involves surgery, radiation and some combination of chemotherapy.
The new publication is the culmination of promising translational results over seven years of studies, starting in preclinical mouse models and then in a clinical trial of 10 pet dogs that had spontaneously developed terminal brain cancer and had no other treatment options. That trial was conducted with owners’ consent in collaboration with the UF College of Veterinary Medicine. Dogs offer a naturally occurring model for malignant glioma because they are the only other species that develops spontaneous brain tumors with some frequency, said Sheila Carrera-Justiz, D.V.M., a veterinary neurologist at the UF College of Veterinary Medicine who is partnering with Sayour on the clinical trials. Gliomas in dogs are universally terminal, she said.
After treating pet dogs that had spontaneously developed brain cancer with personalized mRNA vaccines, Sayour’s team advanced the research to a small Food and Drug Administration-approved clinical trial designed to ensure safety and test feasibility before expanding to a larger trial.
In a cohort of four patients, genetic material called RNA was extracted from each patient’s own surgically removed tumor, and then messenger RNA, or mRNA — the blueprint of what is inside every cell, including tumor cells — was amplified and wrapped in the newly designed high-tech packaging of biocompatible lipid nanoparticles, to make tumor cells “look” like a dangerous virus when reinjected into the bloodstream and prompt an immune-system response. The vaccine was personalized to each patient with a goal of getting the most out of their unique immune system.
“The demonstration that making an mRNA cancer vaccine in this fashion generates similar and strong responses across mice, pet dogs that have developed cancer spontaneously and human patients with brain cancer is a really important finding, because oftentimes we don’t know how well the preclinical studies in animals are going to translate into similar responses in patients,” said Duane Mitchell, M.D., Ph.D., director of the UF Clinical and Translational Science Institute and the UF Brain Tumor Immunotherapy Program and a co-author of the paper. “And while mRNA vaccines and therapeutics are certainly a hot topic since the COVID pandemic, this is a novel and unique way of delivering the mRNA to generate these really significant and rapid immune responses that we’re seeing across animals and humans.”
While too early in the trial to assess the clinical effects of the vaccine, the patients either lived disease-free longer than expected or survived longer than expected.
The 10 pet dogs lived a median of 139 days, compared with a median survival of 30 to 60 days typical for dogs with the condition.
The next step, through support from the Food and Drug Administration and the CureSearch for Children’s Cancer foundation, will be an expanded Phase I clinical trial to include up to 24 adult and pediatric patients to validate the findings. Once an optimal and safe dose is confirmed, an estimated 25 children would participate in Phase 2, said Sayour, an associate professor in the Lillian S. Wells Department of Neurosurgery and the department of pediatrics in the UF College of Medicine, part of UF Health.
For the new clinical trial, Sayour’s lab will partner with a multi-institution consortium, the Pediatric Neuro-Oncology Consortium, to send the immunotherapy treatment to children’s hospitals across the country. They will do this by receiving an individual patient’s tumor, manufacturing the personalized vaccine at UF and sending it back to the patient’s medical team, said Sayour, co-leader of the Immuno-Oncology and Microbiome research program at the UF Health Cancer Center.
Despite the promising results, the authors said one limitation is continued uncertainty about how best to harness the immune system while minimizing the potential for adverse side effects.
“I am hopeful that this could be a new paradigm for how we treat patients, a new platform technology for how we can modulate the immune system,” said Sayour, the Stop Children's Cancer/Bonnie R. Freeman Professor for Pediatric Oncology Research. “I am hopeful for how this could now synergize with other immunotherapies and perhaps unlock those immunotherapies. We showed in this paper that you actually can have synergy with other types of immunotherapies, so maybe now we can have a combination approach of immunotherapy.”
HighlightsGraphic abstractSummary Cancer immunotherapy remains limited by poor antigenicity and a regulatory tumor microenvironment (TME). Here, we create “onion-like” multi-lamellar RNA lipid particle aggregates (LPAs) to substantially enhance the payload packaging and immunogenicity of tumor mRNA antigens. Unlike current mRNA vaccine designs that rely on payload packaging into nanoparticle cores for Toll-like receptor engagement in immune cells, systemically administered RNA-LPAs activate RIG-I in stromal cells, eliciting massive cytokine/chemokine response and dendritic cell/lymphocyte trafficking that provokes cancer immunogenicity and mediates rejection of both early- and late-stage murine tumor models. In client-owned canines with terminal gliomas, RNA-LPAs improved survivorship and reprogrammed the TME, which became “hot” within days of a single infusion. In a first-in-human trial, RNA-LPAs elicited rapid cytokine/chemokine release, immune activation/trafficking, tissue-confirmed pseudoprogression, and glioma-specific immune responses in glioblastoma patients. These data support RNA-LPAs as a new technology that simultaneously reprograms the TME while eliciting rapid and enduring cancer immunotherapy.
- RNA-LPAs mimic dangerous emboli for lymphoreticular entrapment and systemic immunity
- Systemic immunity resets both the peripheral and intratumoral milieu via IFNAR1/RIG-I
- RNA-LPAs are safe and effective tumor re-modulators in canines with spontaneous gliomas
- RNA-LPAs reprogram the TME and elicit adaptive immunity in human GBM patients
Mendez-Gomez, Hector R.; DeVries, Anna; Castillo, Paul; et al.(2024)
RNA aggregates harness the danger response for potent cancer immunotherapy Cell https://doi.org/10.1016/j.cell.2024.04.003
© 2024 Cell Press.
Reprinted under the terms of s60 of the Copyright, Designs and Patents Act 1988.
The Unintelligent Designer: Refuting The Intelligent Design Hoax
ID is not a problem for science; rather science is a problem for ID. This book shows why. It exposes the fallacy of Intelligent Design by showing that, when examined in detail, biological systems are anything but intelligently designed. They show no signs of a plan and are quite ludicrously complex for whatever can be described as a purpose. The Intelligent Design movement relies on almost total ignorance of biological science and seemingly limitless credulity in its target marks. Its only real appeal appears to be to those who find science too difficult or too much trouble to learn yet want their opinions to be regarded as at least as important as those of scientists and experts in their fields.
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The Malevolent Designer: Why Nature's God is Not Good
This book presents the reader with multiple examples of why, even if we accept Creationism's putative intelligent designer, any such entity can only be regarded as malevolent, designing ever-more ingenious ways to make life difficult for living things, including humans, for no other reason than the sheer pleasure of doing so. This putative creator has also given other creatures much better things like immune systems, eyesight and ability to regenerate limbs that it could have given to all its creation, including humans, but chose not to. This book will leave creationists with the dilemma of explaining why evolution by natural selection is the only plausible explanation for so many nasty little parasites that doesn't leave their creator looking like an ingenious, sadistic, misanthropic, malevolence finding ever more ways to increase pain and suffering in the world, and not the omnibenevolent, maximally good god that Creationists of all Abrahamic religions believe created everything. As with a previous book by this author, "The Unintelligent Designer: Refuting the Intelligent Design Hoax", this book comprehensively refutes any notion of intelligent design by anything resembling a loving, intelligent and maximally good god. Such evil could not exist in a universe created by such a god. Evil exists, therefore a maximally good, all-knowing, all-loving god does not.
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Available in Hardcover, Paperback or ebook for Kindle
Illustrated by Catherine Webber-Hounslow.
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